By Fernando Espinal – San Miguel, Avery Myers, and Rocio Ramirez Castro
We opened the conversation about study stimulants with two videos about ADHD medications, Ten facts about adderall (Youtube) and How does Adderall work? (Youtube Video 3 min). Stimulants help ADHD stimulate the brain to release dopamine, this surge of dopamine keeps the person from having to find stimulation in other things such as distractions and thus paves the way for the person to have a more focused attention span. From there we explored the side effects inherent to stimulants, and specifically amphetamine, medications, which can be found at the American Addiction center: Adderall side effects. The main side effects of adderall are common to all stimulants and include: loss of appetite, increased susceptibility to depression,fast heartbeat, and insomnia. After establishing this baseline knowledge, we divided the implications/ramifications/complications of “study drugs” into three categories: physiological, ethical, and economic.
Before we completely dive into those categories, there are a few themes that came up several times throughout the conversation. First and foremost, a complex racial and class understanding is key to understanding the situation surrounding ADHD medications. Diagnosis varies widely across racial lines, even though exports don’t believe there are racial differences in occurrence. More information on the demographic aspect of ADHD diagnosis can be found in this study, Twenty-Year Trends in Diagnosed Attention-Deficit/Hyperactivity Disorder Among US Children and Adolescents, 1997-2016. Furthermore, although we focus on kids and adolescents because that’s where these drugs are most visible, adults are increasingly diagnosed with and treated for ADHD. The newly passive population of kids taking these medications is also aging. An investor report from Shire, the makers of the leading stimulant ADHD medications, claims, “The adult segment of the ADHD market is not only the fastest-growing market segment but also has the potential to be significantly larger than the pediatric segment, a total of 9.9 million patients of which 7.5 million are untreated.” The present race and age demographic impacts the stigma of “study stimulants” and the oncoming demographic shift upwards in age will increase medical knowledge/exploration of both the drugs themselves and side effects on adult bodies. An example of the increased adults on a medication generating increased research for that medication is the article Attention-Deficit/Hyperactivity Disorder Medication Prescription Claims Among Privately Insured Women Aged 15–44 Years — United States, 2003–2015, which says, “The percentage of reproductive-aged women who filled a prescription for any ADHD medication increased over time for all age groups and geographic regions… From 2003 to 2015, the largest increase in ADHD prescriptions filled occurred among women aged 25–29 years (700%).” The rise in usage they found perpetuates the research process because that demographic has specific concerns. For example, the rise in women of childbearing age leads to the study’s claim that, “additional research on ADHD medication safety during pregnancy is warranted to inform women and their health care providers about any potential risks associated with ADHD medication exposure before and during pregnancy.”
In the physiological category, we provided an NPR article describing the results of a study on ADHD medication and sleep, Common ADHD Medications Do Indeed Disturb Children’s Sleep, and a study of a specific medication on various nutrition metrics, The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder. The NPR article found that because of overstimulation in their brains as a result of medication, children are finding it difficult to unwind and relax before being able to sleep. The study found “A statistically significant decrease from baseline to endpoint was evident in weight (p < 0.001), body mass index (p < 0.001), fasting total cholesterol (p = 0.011), low density lipoprotein cholesterol (p = 0.044), high density lipoprotein cholesterol (p = 0.015) but not triglycerides, or blood glucose. Significant reductions were also observed in leptin (p = 0.047), but not in ghrelin, adiponectin, or resistin levels.”We asked what do these two studies suggest about the physical development of kids and adolescents on these medications? The answer, after some discussion, is that the deficits described in these articles and the aforementioned Adderall side effects combine to deny kids the most fundamental resources mental and physical growth and development. We asked the class consider themes of intersections of mania and hyperactivity, holistic wellness, diagnostic process before asking, why do you think the second study examines the comorbidity of ADHD with a mood disorder? Answers to this question are less straight forward, but it sparked conversation about the possible misdiagnosis between mood disorders featuring mania and personality/learning disorders featuring hyperactivity, especially when diagnosis is being done more and more casually (a phenomenon we will explore in the ethics section).
The previous articles and discussion questions were assigned before class. For our in class discussion on the physiology of study stimulants, we introduced the subject of withdrawals. We provided an article, Lisdexamfetamine (Vyvanse) Withdrawal in Children with Orofacial Cleft and Attention-Deficit/Hyperactivity Disorder, containing two essential points; first, that stimulants are the first line of therapy for ADHD in children older than 6, and second, withdrawal symptoms in children are variable and different than in their adult counterpart. This article is a case study of an eight year old boy who stopped taking his vyvanse for a surgical procedure and finds that withdrawal symptoms are absolutely associated with consistent use of stimulant medications at any age. However, withdrawal symptoms in children is not news, so we asked: what separates these drugs and children from other cases of early childhood addiction? We provided a statistic from another study, Twenty-Year Trends in Diagnosed Attention-Deficit/Hyperactivity Disorder Among US Children and Adolescents, 1997-2016, which was that non-Hispanic white people formed 49% of the sample population and 61% of the diagnosed-w-ADHD population. The class quickly acknowledged the difference in stigma between the previously held concept of child addicts as born addicts to poor, nonwhite, pregnant drug users and children who developed their addiction as a result of prescribed ADHD meds. While these two parties might seem different in circumstance, separate from and perhaps even justifying their differences in stigma, but both groups of kids are facing the physiological consequences of inundation with a substance of their parent’s choice. You could even argue the second situation is worse (to be clear, neither is good) because a pregnant drug user imparts the physiological consequences of their substance use on themselves and their child, but a parent demanding their child take prescription stimulants for years imparts those consequences on only their child. It is important to note that the same parents creating this situation are the ones with enough privilege to prioritize the study of withdrawal in children, but the oncoming explosion of research on the subject reflects their privilege, not any particular change in the severity of the situation.
We explored the role of parents and doctors, as opposed to patients, further in the ethics section. Before class we assigned a Psychiatric Times article about the diagnosing/prescribing process, Problems of over prescribing and Over diagnosis in ADHD, and an NPR article about unprescribed use and the culture surrounding it, NPR Neurologist Warn Against ADHD Drugs to Help Kids study. The first NPR article outlines the major concerns of the regulated market for ADHD medications, those being that the regulated market is incentivized by the pharmaceutical companies that produce the drugs to prescribe as much of the medication as possible for profit, which leads to overprescribing medicine and falsely diagnosing ADHD. The second article does the same for the unregulated market, those being that because of overprescription, among other reasons, patients are selling their prescriptions to others to whom it has not been prescribed.
The first question we posed was simply, How does the phrase “pediatric neuroenhancement”, from the first article, make you feel? The general consensus seemed to be, simply put, bad. The idea that parents trying to “enhance” their children biochemically occurs so often it became a known and named phenomenon is extremely disturbing. For the second question, we directed our attention to a specific quote, also from the first article, “This type of evaluation may result in overdiagnosing ADHD, or underidentifying ADHD in children with complex and comorbid presentations.” We asked the class what this quote says about the priorities of psychiatrists prescribing these drugs, and they responded that the quote indicates a profit-centered, not patient-centered, approach. Not to mention, the streamlining of ADHD diagnostic criteria means that complex presentations of ADHD don’t get diagnosed, and the diagnostic criteria stagnates with an incomplete picture or begins to reflect the presentation of neurotypicals, or, even more confusingly, those with drug seeking tendencies. For the third question, we also pulled a quote to consider, this time from the NPR article,“‘We don’t believe that doctors are supposed to be drug dispensers for healthy people,’ says William Graf, a professor of pediatrics and neurology at the Yale School of Medicine. ‘This is an ethics issue.’”Considering Graf’s opinion, we asked: Is this a compelling argument? Is selling or sharing prescription medicine inherently unethical? Although there was some disagreement on when selling prescription medicine on the black market has the potential to be exploitative, the class seemed to agree that the realities of the US pharmaceutical industry (particularly at its intersection with poverty) offer profound economic incentives to buying AND selling ADHD medications.
For our in class content in the ethics category, we revisited a reading from the economics section (which this blog post will discuss last). The reading was a news article from Drug Discovery & Development entitled Court Upholds Shire Vyvanse Patents, and it contains the following excerpt:
Shire’s Vyvanse patents expire in 2023 but Shire recently announced that it has agreed to a Written Request by the U.S. Food and Drug Administration (FDA) to conduct pediatric clinical studies to investigate the potential use of Vyvanse for the treatment of ADHD in preschool-age children, ages four to five. Upon FDA confirmation of a timely submission and review of data that adheres to the requirements of the Written Request, Shire will be entitled to the benefits of the Best Pharmaceuticals for Children Act, including a six-month extension to the exclusivity afforded by Shire’s patents for Vyvanse.
Further research into the Best Pharmaceuticals for Children Act (BPCA) revealed its sister act, the Pediatric Research Equity Act (PREA). The Best Pharmaceuticals for Children Act (2002), “grants an additional 6 months patent exclusivity to encourage the pharmaceutical industry to perform pediatric studies to improve labeling for patented drug products used in children and instructs NIH to prioritize therapeutic areas and sponsor clinical trials and other research for off-patent drug products that need further study in children.” The Pediatric Research Equity Act, “gives FDA the authority to require pediatric studies in certain drugs and biological products. Studies must use appropriate formulations for each age group. The goal of the studies is to obtain pediatric labeling for the product.” Overall, these two acts incentivize and require child research. This raised a few questions: What are the potential risks and benefits to incentivizing experimenting on children? Are any particularly relevant to ADHD medications? The class came to understand these policies are can be good for increasing the safety of children’s medications or prioritizing childhood conditions, but the extension of an ADHD medication to a four and five year old market defies common sense. There are, however, major economic reasons to defy common sense in this case.
ADHD medications are a ridiculously profitable market. One of the readings assigned before class was a list of the prices of ADHD medications in 2005, Wholesale Prices of Prescription ADHD Medicines. We drew attention to a few significant details of this list, focusing particularly on the price of vyvanse then and now. The price then was $205.00 and the price of vyvanse today is $471.33. Without insurance, the price goes no lower than $308.49 with third party coupons (such as SingleCare or GoodRx). With insurance, the price tends to be around $60.00 and can go to an absolute minimum of $30.00 with the combination insurance and a coupon directly from the vyvanse website. $205.00 in 2005 has the same purchasing power as $277.57 in 2020, so we asked what factors could account for the rest of the price increase? The primary answer is simply that their exclusive patent position allows them to. The aforementioned Drug Discovery & Development news article, Court Upholds Shire Vyvanse Patents, was also an assigned reading for this section. The article essentially described how Shire’s vyvanse patents were affirmed after multiple and combined attacks from other pharmaceutical companies. The patents were upheld for several reasons, one being that, “the Court found “defendants have not offered evidence sufficient to prove [method of treating ADHD] claim 4 of the ’486 patent is invalid due to obviousness or anticipation.” We asked the class if there are any dangers to trying to draw a hard legal line on how “obvious” a chemical compound is, and they responded that the specific associated dangers of doing so simply reflect the overall absurdity of patenting a chemical compound. In other words, no aspect of patenting a chemical compound, something inherently inseparable from its potential to occur naturally, is entirely reasonable.
Before introducing the in class content, we asked the class if they had ever heard of Shire, the producer of adderall and vyvanse, before this class. None of them had, which is both completely in line with Shire’s intentions and completely shocking due to their impact on the ADHD market and the pharmaceutical industry as a whole. A brief history: Shire was founded by 5 men in 1986, listed on the London Stock Exchange in 1996, and listed on Nasdaq 1998. They began acquiring other pharmaceutical companies in 1997 (Pharmavene for £105 million) and did not stop until they became the largest global biotech company focused solely on rare diseases in 2016 (Baxalta for $32 billion). They were purchased by Takeda in 2018 for $62 billion. Their life cycle can be followed via an online archive of annual and interim investor reports that begin with the last 6 months of 1997. The reports from 2001 and 2007 were used heavily in this presentation. The important questions to keep in mind through this slightly convoluted series of acquisitions and new medications are 1. How did Shire’s early 2000s decisions demonstrate changes in/actively change the pharmaceutical industry? And 2. Why do you think pharmaceutical companies specialized in categories of illness (such as neuroscience or oncology)? How does access to a particular categorical market travel through pharmaceutical companies? After providing these questions, we presented the following information on Shire and ADHD medications. This information is largely from an online archive of annual and interim financial reports that begin with the last 6 months of 1997 found on Shire’s website. Shire introduced Adderall in 1996 (although it was technically debuted by Richwood Pharmaceutical in ‘95) and its once-a-day counterpart Adderall XR (extended release) in 2001. An excerpt from the 2001 investor report connects these two medications directly to Shire’s first two acquisitions, Pharmavene Pharmaceuticals and Richwood Pharmaceuticals, in 1997:
“From Richwood Pharmaceutical came one outstanding product, ADDERALL, for the treatment of ADHD, which is now successfully marketed by Shire’s US sales force. Pharmavene, now known as Shire Laboratories, Inc, took on ADDERALL XR (a once a day product) development projects. Today, Shire Laboratories, Inc. plays a very important role in the future success of Shire.”
It is worth noting that extended release products would become Shire’s greatest source of revenue. It is also worth noting, with an excerpt from the same expense report, how Shire changed its overall business strategy in the late 90s/early 2000s:
“[Shire] set out to in-license specialty pharmaceutical products at the pre-clinical or later stages of clinical development and, at the same time, to develop or acquire specialised sales forces that could effectively market these products direct to specialist doctors in the world’s major markets.”
This quote is particularly relevant (and answers the first discussion question) because it recalls an overall shift, one we discussed in previous classes, in economic strategy among most pharmaceutical companies away from research and development and towards market spending. A final, less relevant but perhaps more disturbing detail from the same report:
“Royalty revenue increased 7% to $145.2 million in 2001 compared to $135.5 million in 2000. The Group receives royalties from GlaxoSmithKline (GSK) on the worldwide sales of 3TC and ZEFFIX.”
These royalties are from patents on medications that treat HIV/AIDS. Patents became the name of Shire’s game in the first decade of the millenium as the adderall patents had expired. A 2007 investor report contains the excerpt:
“The Group anticipates that there will be one or more generic competitors of ADDERALL XR in the ADHD market beginning April 2009. ADDERALL XR is, in revenue terms, Shire’s most significant product representing 42% of total revenues (2006: 48%). The Group expects that sales of VYVANSE will partially offset any decline in sales of ADDERALL XR”
To conceptualize 42% of revenue, consider that sales for ADDERALL XR in 2007 were up 19% to $1,030.9 million. No other product even approached 200 million. Shire, “consistent with its stated focus on the growing ADHD market,” and in clear repetition of the method that delivered adderall so profitably, had purchased New River Pharmaceuticals for $2.6 billion in 2007, which gave them ownership of Vyvanse. They were also beginning research on another ADHD medication called INTUNIV. They moved to Ireland in 2008 for taxation reasons and began steadily acquiring companies again in 2010-2016 when they merged with Baxalta. This is an important purchase because, as an article in Genetic Engineering and Biotechnology News writes, “Shire brings to the combined company products in gastrointestinal/endocrine diseases; hereditary angioedema (HAE); neuroscience; and lysosomal storage diseases. Baxalta contributes products in its specialty areas of hematology, immunology, and oncology.” (Shire, Baxalta Tie the Knot in $32B Merger). This is a perfect example (and answer to the second question) of why pharmaceutical companies specialize, which is because producing a variety of products for one condition/group of conditions ensures revenue from that demographic no matter what they “choose” AND to make themselves more valuable for purchase. However, this specialization encourages consolidation, and tracking the market claim over stimulant ADHD medications from Richwood to Tapeka demonstrates how those claims move by means of acquisition. That is how Shire contributed to, then was absorbed by, the overarching structure of the present pharmaceutical industry as well as exploded the “ADHD market” with little to no regard for the ethical or physiological consequences.
Bibliography
-Cunningham, A. (2015, November 24). Common ADHD Medications Do Indeed Disturb Children’s Sleep. From https://www.npr.org/sections/health-shots/2015/11/24/457137288/common-adhd-medications-do-indeed-disturb-childrens-sleep
-Mcintyre, R. S., Alsuwaidan, M., Soczynska, J. K., Szpindel, I., Bilkey, T. S., Almagor, D., … Kennedy, S. H. (2013). The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder. Human Psychopharmacology: Clinical and Experimental, 28(5), 421–427.
– Connor, D. F. (2011, August 11). Problems of Overdiagnosis and Overprescribing in ADHD. Retrieved from https://www.psychiatrictimes.com/adhd/problems-overdiagnosis-and-overprescribing-adhd
-Shute, N. (2013, March 14). Neurologists Warn Against ADHD Drugs To Help Kids Study. Retrieved from https://www.wbur.org/npr/174193454/neurologists-warn-against-adhd-drugs-to-help-kids-study– Editor, Drug Discovery Trends, and Drug Discovery Trends Editor. Court Upholds Shire Vyvanse Patents. 11 Oct. 2019, www.drugdiscoverytrends.com/court-upholds-shire-vyvanse-patents